GYY4137 alleviates sepsis-induced acute lung injury in mice by inhibiting the PDGFRβ/Akt/NF-κB/NLRP3 pathway.

Affiliation

Li J(1), Ma J(2), Li M(2), Tao J(3), Chen J(2), Yao C(4), Yao S(5).
Author information:
(1)Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Critical Care Medicine, The First Affiliated Hospital, College of Medicine, Shihezi University, Shihezi 832000, China.
(2)Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
(3)Department of Orthopedics, The Third Affiliated Hospital, College of Medicine, Shihezi University, Shihezi 832000, China.
(4)Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: [Email]
(5)Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: [Email]

Abstract

AIMS: GYY4137 [GYY, morpholin-4-ium-4-methoxyphenyl (morpholino) phosphinodithioate] is a novel and perfect hydrogen sulfide (H2S) donor that is stable in vivo and in vitro. H2S, along with CO and NO, has been recognized as the third physiological gas signaling molecule that plays an active role in fighting various lung infections. However, the mechanism by which GYY4137 affects cecal ligation and puncture (CLP)-induced acute lung injury (ALI) is not understood. This study aimed to investigate whether GYY4137 inhibits the activation of the pyrin domain-containing protein 3 (NLRP3) inflammasome by inhibiting the PDGFRβ/Akt/NF-κB pathway. MAIN METHODS: The model of CLP-induced ALI was established in vivo. The mice were subsequently treated with GYY4137 (25 μg/g and 50 μg/g) to simulate the realistic conditions of pathogenesis. Western blotting and immunohistochemical staining were used to examine protein expression, hematoxylin and eosin staining was used for the histopathological analysis, and the levels of inflammatory factors were determined using enzyme-linked immunosorbent assays (ELISAs). KEY FINDINGS: GYY4137 significantly increased the 7-day survival of mice with septic peritonitis and protected against CLP-induced ALI, including decreasing neutrophil infiltration, improving sepsis-induced lung histopathological changes, diminishing lung tissue damage, and attenuating the severity of lung injury in mice. The protective effect of GYY4137 was undoubtedly dose-dependent. We discovered that GYY4137 reduced the levels of the p-PDGFRβ, p-NF-κB, ASC, NLRP3, caspase-1, and p-Akt proteins in septic mouse lung tissue. Akt regulates the generation of proinflammatory cytokines in endotoxemia-associated ALI by enhancing the nuclear translocation of NF-κB. SIGNIFICANCE: These results indicate a new molecular mechanism explaining the effect of GYY4137 on the treatment of CLP-induced ALI in mice.